PTK787/ZK222584 Combined with Interferon Alpha and 5-Fluorouracil Synergistically Inhibits VEGF Signaling Pathway in Hepatocellular Carcinoma

Background

The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus remains poor. We previously reported the beneficial effects of interferon alpha (IFN) and 5-fluorouracil (5-FU) combination therapy for these patients. We showed that the mechanism of therapy was regulation of vascular endothelial growth factor (VEGF). Here, we combined IFN/5-FU therapy with the VEGF receptor–selective inhibitor PTK787/ZK222584 (PTK/ZK) and examined the antitumor effects and the mechanism of action.

Methods

We studied two HCC cell lines, PLC/PRF/5 and HuH7, and a human umbilical vein endothelial cell line, HUVEC. We studied the effects of IFN/5-FU with or without PTK/ZK in growth inhibition assays, immunohistochemistry, Western blot analysis, and immunocytochemistry.

Results

In a HuH7 xenograft model, the combination of PTK/ZK and IFN/5-FU significantly inhibited proliferation, induced apoptosis, decreased microvessel density, reduced the number of tumor cells that expressed VEGF receptor 2 (VEGFR-2), and repressed the phosphorylation of Akt in vivo. In HCC cells and HUVECs in vitro, IFN/5-FU plus PTK/ZK repressed the expression of VEGFR-2 and repressed the phosphorylation of VEGFR, Akt, Erk, and p38MAPK.

Conclusions

VEGF signaling inhibition enhanced the antitumor effects of IFN/5-FU therapy on HCC cells and endothelial cells via Erk, Akt, and p38MAPK pathways.

     

Subchondral cysts in dysplastic osteoarthritic hips communicate with the joint space: analysis using three-dimensional computed tomography

Introduction

Bone cyst formation in hips increases as osteoarthritis worsens. Although bone cysts in hips have been described in many studies, their etiology remains unclear and under debate. The purpose of this study was to investigate the communication between a bone cyst and the joint space, as well as the relationship between the severity of osteoarthritis and the formation of subchondral bone cysts in dysplastic hips.

Method

We studied bone cysts from 150 dysplastic hips in 97 patients by computed tomography (CT) and plain radiography. We investigated the distribution of the bone cysts and the presence or absence of a communication path between the cysts and the joint space by three-dimensional (3D) CT.

Result

Of the 150 hips, 94 acetabula and 55 femoral heads were found to contain cysts. Of the 94 hips containing acetabular cysts, 89 and 5 hips showed black lines and gray lines connecting the cyst and the joint space, respectively, on 3D-CT. The rate of cyst presentation in the hip increased as the joint space became narrower. The number of hips that possessed cysts in the anterior and/or middle portion was significantly higher than that in the posterior portions.

Conclusion

Bone cysts in dysplastic osteoarthritic hips were found to communicate with the joint space in all cases. This suggests that the formation and enlargement of the cysts in dysplastic hips may be greatly influenced by the joint fluid. Cyst formation was initially observed in the anterior acetabulum, gradually progressing to involve the entire joint, including the posterior acetabulum and the femoral head, with worsening of the osteoarthritis.     

Intrathoracic Esophagogastric Anastomosis Using a Linear Stapler Following Minimally Invasive Esophagectomy in the Prone Position

Background

Minimally invasive esophagectomy (MIE) in the prone position typically includes thoracoscopic mediastinal dissection and laparoscopic gastric tube construction, followed by esophagogastric anastomosis in the neck. We introduced an intrathoracic esophagogastric anastomosis using linear staplers.

Technique

The lower mediastinal dissection and the gastric tube construction are done in the laparoscopic part of the operation. The esophagus is transected at the cranial level of the aortic arch after the completion of the upper mediastinal lymph node dissection in the prone position. The excess length of the gastric tube is sacrificed before making the anastomosis. Side-to-side esophagogastric anastomosis is performed using a 35-mm endoscopic linear stapler. The entry hole is closed with hand suturing using the posterior and the axillary port.

Results

Twenty-six patients with middle or lower esophageal tumor underwent MIE with an intrathoracic anastomosis. The mean thoracoscopic procedure time was 302 min. One patient had an anastomotic leakage, which was successfully managed with drainage. There has been no anastomotic stenosis. Pneumonia was observed in two patients. There was no mortality.

Conclusions

MIE with an intrathoracic linear-stapled anastomosis with the patient in the prone position is safe and feasible.     

New Surgical Approach to Large Splenorenal Shunt in Living Donor Liver Transplantation: Diversion of SMV and SPV Blood Flow

Introduction

The management of a large splenorenal shunt is important because it affects recipient outcome, particularly in living donor liver transplantation.

Methods

To manage large splenorenal shunts in living donor liver transplantation, we diverted superior mesenteric vein and splenic portal vein blood flow by ligation at the root of the splenic portal vein.

Result

This procedure was applied for five patients in whom superior mesenteric vein blood flow had been completely stolen by a splenorenal shunt preoperatively. Postoperative course was excellent in all cases.

Conclusion

This technique completely prevents morbidity related to large splenorenal shunts after living donor liver transplantation.     

Decreased expression of aquaporin 2 in the collecting duct of mice lacking the vasopressin V1a receptor

Background

Vasopressin V1a receptor null (V1aR^?/?) mice recently showed incomplete urinary concentration due to higher urine volume during control and water diuresis (euhydration), but showed normal response during dehydration (Aoyagi et al., Am J Physiol 295: F100–7, 2008).

Methods

Water balance, plasma vasopressin, plasma and urine osmolality, and aquaporin 2 (AQP2) expression in the kidney of wild-type (WT) and V1aR^?/? mice were therefore further examined using improved methods of urine collection (urinary bladder urine).

Results

V1aR^?/? mice demonstrated a lower urine osmolality (3,360 ± 138 vs. 3,610 ± 47 mOsm/kgH₂O) and a higher plasma osmolality (354.3 ± 1.3 vs. 342.5 ± 1.5 mOsm/kgH₂O) after dehydration for 24 h compared to WT mice (P < 0.05). In contrast, the plasma vasopressin concentration was significantly (P < 0.001) higher in the V1aR^?/? mice (48.8 ± 4.8 vs. 22.1 ± 2.4 pg/ml). On the other hand, although the AQP2 protein expression in the kidney was increased after dehydration, the basal (control) and dehydration-induced AQP2 protein levels were significantly lower in V1aR^?/? mice compared to WT mice (by Western blotting). Staining by an anti-AQP2 antibody in the luminal membrane of the collecting ducts was increased in both V1aR^?/? and WT mice after dehydration, but was relatively weaker in the V1aR^?/? mice (by immunohistochemistry). Moreover, urinary excretion of AQP2 protein, an index of the luminal AQP2 expression, was significantly (P < 0.05) lower in the V1aR^?/? mice.

Conclusion

V1aR signaling may be fundamentally important for the expression of AQP2 in the collecting ducts during control conditions and dehydration.     

Prompt institution of percutaneous cardiopulmonary support managed perioperative refractory vascular spasm after isolated coronary artery bypass grafting surgery

A 51-year-old Japanese male underwent on-pump coronary artery bypass grafting surgery. After weaning from cardiopulmonary bypass (348 min), sudden bradycardia and hypotension occurred, followed by ventricular fibrillation. Although defibrillation and infusion of catecholamine restored sinus rhythm, transesophageal echocardiography demonstrated severely reduced contraction of both ventricles, and perioperative vascular spasm was suspected. As vascular spasm was refractory to medications, percutaneous cardiopulmonary support (PCPS) system was quickly instituted under cardiac massage. Coronary angiography revealed vascular spasm of not only the native coronary arteries but also the implanted left internal thoracic artery. After 3 days of full hemodynamic assist, PCPS was withdrawn with no obvious abnormalities in regional wall motion by transesophageal echocardiography. The patient was extubated on postoperative day 6 with no impaired brain function. In this case, the immediate diagnosis of refractory vascular spasm by transesophageal echocardiography and full cardiocirculatory assistance by PCPS helped to save the life of the patient.